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KETAMINE TREATMENT FOR NON-MOTOR SYMPTOMS OF PARKINSON'S DISEASE

Gerard Sanacora — Mina Ansari1, Lauren Astorino1, Katherine Cioe1, Marcus Hughes,1, Sarah Jefferson1, Sina Nikayin1, Brian Pittman1, Veronica Santini1, Sherab Tsheringla1, Sule Tinaz1, Sophie Holmes1 1Yale University

2026 ASCP Annual Meeting

Background

Parkinson’s disease (PD) is a neurodegenerative disorder characterized not only by motor impairment but also significant reductions in overall quality of life secondary to the presence of non-motor symptoms such as apathy, anhedonia, anxiety, and pain. Advances in our understanding of PD pathophysiology have increased, revealing promising new targets for interventions aimed at alleviating non-motor symptoms. Emerging evidence suggests that impaired regulation of synaptic plasticity in brain networks outside of primary motor circuits could contribute to these burdensome features of the disease. Ketamine has been shown to enhance synaptic plasticity in brain regions related to motivated behavior and reward sensitivity, as well as well-established antidepressant effects in major depressive disorder. Together, there is strong rationale for investigating ketamine as a treatment for non-motor symptoms in PD.

Methods

In this single-site phase II clinical trial funded by the Michael J Fox Foundation, 51 participants with confirmed PD and depressive symptoms meeting criteria for a current major depressive episode [Montgomery Asberg Depression Rating scale (MADRS) ≥15] were randomized to treatment with either IV ketamine 0.5mg/kg/40mins or IV saline placebo delivered over 40mins at an interval of 2 times per week for 3 weeks. The primary outcome measure was change in MADRS score from baseline to end-of-treatment (EOT) [24-72hrs after last dose of study drug]. Other key measures included, MADRS determined response [≥50% reduction in score] and remission [score ≤10] at EOT and 1-month after last study drug administration. Additional measures assessing non-motor symptoms, inluding apathy (Starkstein Apathy Scale, SAS), Anhedonia (Snaith-Hamilton Pleasure Scale, SHAPS), anxiety (State-Trait Anxiety Inventory, STAI), and pain (King’s Parkinson’s Disease Pain Scale, KPPS) were also collected and analyzed. To evaluate the adequacy of masking, patients and research staff were asked at EOT to guess treatment allocation.

Results

There were no meaningful baseline differences in age, sex distribution, Parkinson’s motor symptom severity, depressive symptom severity, or cognitive impairment at baseline. Fifty of the 51 participants randomized (25 placebo, 26 ketamine) received at least one treatment and completed the study. Ketamine was associated with transient increases in systolic and diastolic blood pressure. However, no patients were discontinued from treatment due to cardiovascular events. No evidence of decreased oxygen saturation was observed in the ketamine group compared to the placebo group. One Serious Adverse Event was reported in a participant receiving placebo, consisting of new onset atrial fibrillation and metabolic abnormalities. Most common treatment emergent adverse events in the study were headache (22% ketamine, 31% placebo), nausea (12% ketamine, 12% placebo), dizziness/faintness (8% ketamine, 10% placebo), and early morning awakenings (10% ketamine, 2% placebo). No Treatment emergent adverse events led to withdrawal. Ketamine was associated with a significantly greater reduction in MADRS score from baseline to the EOT compared to placebo, with a significant group × time interaction on MADRS (F=5.26, p=0.001). From baseline to post-treatment, MADRS scores decreased by an average 16-points in the ketamine group, compared with 10-points in the placebo group (p=0.006). Additional outcome measures showed the effect was sustained at 1-month follow-up (p=0.002) and that response rates were significantly higher with ketamine (73%) compared with in the placebo group (38%) at EOT (Chi =0.01); this difference also persisted at the 1-month follow-up (69% vs 29%; Chi =0.005). Significant differences were also observed for remission rates at EOT (54% vs 25%; Chi =0.04) and at 1-month follow-up (50% vs 17%; Chi =0.01). Measures of other associated non-motor symptoms also showed significant and clinically meaningful improvements in apathy (SAS) (p=0.015) and anxiety (STAI) (p=0.005) at EOT. Both measures showed trends towards sustained benefit at 1-month follow-up (SAS, p=0.07; STAI, p=0.06). Improvement in anhedonia approached significance at post-treatment (p=0.055). Pain, assessed using the KPPS improved over the treatment period in both groups, but appeared to rebound at the 1-month follow-up for participants in the placebo group but not the ketamine treated group, resulting in a 6.3-point difference between groups at that timepoint. 78% of the patients correctly guessed treatment assignment. Of the patients receiving placebo 62% correctly guessed assignment while 92% of those allocated to ketamine correctly guessed treatment assignment. Clinicians correctly guessed assignment for 90% of participants.

Discussion

Overall, this phase II study provides strong preliminary evidence that IV ketamine delivered at 0.5mg/kg/40mins twice a week for three weeks is generally safe and can provide significant and clinically meaningful benefits to patients suffering with a range of non-motor symptoms commonly associated with PD. These treatment effects were evident despite a relatively high level of placebo response. Measures of depression severity, apathy, and anxiety all showed improvement following treatment and the benefits were largely sustained at the 1-month follow up time point. There was additional evidence of beneficial effects on anhedonia and pain at the end of treatment and the one-month follow up respectively. Imperfect treatment allocation masking was suggested by both patient and study team guesses. However, allocation guesses were collected at the end of treatment, and may therefore have been influenced not only by the transient effects of ketamine but also by the longer-term response experienced or observed during the study. Interestingly, despite the likely effect of unblinding, a relatively large placebo response was still observed and adverse events were relatively similar between groups. In sum, the data provide strong preliminary evidence of ketamine’s ability to provide benefits to patients suffering from a range of nonmotor symptoms associated with PD. Considering the growing prevalence and burden of PD, and the large unmet need for effective treatments of the non-motor symptoms associated with PD, it appears future studies examining Ketamine’s potential role in the overall management of PD for some individuals are warranted.